Measurement of daily cholesterol synthesis rates in man can currently performed by time-consuming procedures which are not applicable to rapid determinations of the effects of drug/dietary interventions on cholesterol synthesis. The proposed research project is designed to determine the potential clinical applicability of utilizing freshly isolated blood mononuclear leukocytes for the in vitro assay of rates of whole body cholesterol synthesis as related to the individual patient response to drug and/or dietary interventions. Mononulcear leukocytes will be isolated from patients during control and following treatment with interventions known to affect whole body cholesterol synthesis. The sterol synthetic rate of the isolated cells will be related to whole body sterol balance during both periods. The mononuclear cells will be fractionated into lymphocytes and monocytes in order to elucidate which cell population is more responsive to in vivo and in vitro manipulations. Studies will be performed to determine the effect of each intervention on cellular sterol composition, cyclic AMP levels, and the activities of 3-hydroxy-3-methylglutaryl coenzyme A reductase and acyl-cholesterol acyl transferase. In vitro studies will be performed investigating the regulation of mononuclear cell sterol metabolism under conditions of induction of sterol synthesis by incubation in delipidized medium and addition of mitogens to define the metabolic and genetic regulatory mechanisms operative. These studies are expected to provide the basis for analysis of sterol synthetic rates and their fluctuations in man by a rapid, non-isotopic procedure requiring only a single blood sample. In addition, the data will provide new information regarding the in vivo control mechanisms involved in the regulation of sterol synthesis in nonhepatic cells and the mechanisms whereby this regulation may be altered in patients with hyperlipidemia and its associated risk of cardiovascular disease.